Pharmaceutical compositions of 6-chloro-7-sulfamyl-3, 4-dihydro-2h-[1, 2, 4]-benzothiadiazine 1, 1-dioxide and an indole alkaloid of the apocynaceae family



United States Patent PHARMACEUTICAL COMPOSITIONS 0F 6-CHLO- R0 7 SULFAMYL 3,4 DIHYDRO 2H [1,2,4]- BENZOTHIADIAZINE 1,1 DHUXIDE AND AN ENDQLE ALKALOID 013 THE APOCYNACEAE FAMILY George de Stevens and Lincoln Harvey Werner, Summit, N..l., assiguors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Qriginal application Sept. 12, 1963, Ser. No. 308,327, new Patent No. 3,288,678, dated Nov. 29, 1966. Divided and this application Mar. 18, 1966, Ser. No. 535,357 The portion of the term of the patent subsequent to Nov. 29, 1983, has been disclaimed 7 Claims. (Cl. 167-65) ABSTRACT 0F THE DISCLOSURE Compositions (and methods for their preparation) useful in the treatment of hypertension and containing essentially 1) 6 chloro 7 sulfamyl 3,4 dihydro 2H- [1,2,4]-benzothiadiazine-1,1-dioxide and (2) an indole alkaloid of the Apocyuaceae family, such as resperine.

This application is a division of application Ser. No. 308,327, filed Sept. 12, 1963, now US. Patent 3,288,678 issued Nov. 29, 1966 which in turn is in part a continuation of application Ser. No. 845,623, filed Oct. 12, 1959; which in turn is in part a continuation of application Ser. No. 791,831, filed Feb. 9, 1959; which in turn is in part a continuation of application Ser. No. 764,482, filed Sept. 29, 1959; which in turn is in part a continuation of application Ser. No. 751,620, filed July 29, 1959; which in turn is in part a continuation of application Ser. No. 740,- 582, filed June 9, 1958; which in turn is in part a continuation of application Ser. No. 727,242, filed Apr. 9, 1958; which in turn is in part a continuation of application Ser. No. 718,452, filed Mar. 3, 1958 all of which are now abandoned.

This invention relates to and has for its object the provision of compositions (and methods for their preparation), useful in the treatment of hypertension. These compositions contain essentially (1) 6-chloro-7-sulfarnyl-3,4- dihydro-2H-[1,2,4]-benzothiadiazine-1,l-dioxide and (2) an indole alkaloid of the Apocynaceae family, such as reserpine.

One may desirably use about 1 to about percent of 6-chloro-7-sulfamyl-3,4-dihydro-2H-[1,2,4] benzothiadiazine-l,1-dioxide to about 0.005 to about 0.5 percent of indole alkaloid (e.g. reserpine, deserpine or rescinnamine). Preferred proportions are about 2.5 to about 10 percent of the dihydro benzothiadiazine-l,1-dioxide to about 0.01 to about 0.04 percent of indole alkaloid (particularly about 2.5 percent benzothiadiazine-1,1-di oxide to about 0.01 percent indole alkaloid).

The tablet, capsule or pill provides a convenient oral form of administration of the compositions of the invention. These forms may be compounded to contain about 10 to about 200 mg. (more particularly about to about 100 mg.) of dihydro benzothiadiazine-l,l-dioxide and about 0.05 to about 5.0 mg. (more particularly about 0.1 to about 0.4 mg.) of reserpine, deserpidine or rescinnamine. Tablets may, of course, be scored to provide for fractional dosages, if desire-d. Complete tablets (or capsules) containing about 0.1 mg. reserpine or deserpidine or 0.5 mg. rescinnamine and about 25 mg. dihydro benzothiadiazine- 1,1-dioxide are convenient for administration and may normally be administered 1-3 times daily, but administration may vary with the needs of each particular patient and is best determined by the physician in each case.

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The inert fillers and binders which are normally employed in the art of tablet (or capsule) making may be used in formulating tablets (or capsules). Examples of these materials are corn starch, lactose, stearic acid, talc, magnesium stearate, tragacanth, acacia, etc. The quantitles of these ingredients may vary widely in accordance with the dictates of those skilled in the art, and depend largely upon the kind, i.e. soft or hard, and size of tablet which is required. Encapsulation may also be effected, using the same excipients as those used for tablets. At any rate, as has been indicated above, the compounding is eliected in exactly the same manner as that normally employed in the art. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law, may be used for esthetic purposes or as a means of identification.

Salts of the diuretic which may be used in this invention are therapeutically useful salts with metals, particularly the alkali metal salts, such as those with sodium or potassium. Monoor poly-salts may be formed.

The 6 chloro 7 suliamyl 3,4 dihydro 2H- [1,2,4]-benzothiadiazine-1,1-dioxide used in this invention may be prepared as shown in the recited examples of copending application Ser. No. 764,482, of common assignment, the continuation of which is now U.S. Patent No.

3,103,645, one of which are given below:

Example A A mixture of 2.9 g. of 5-chloro-2,4-disulfamyl-aniline in 15 ml. of anhydrous diethyleneglycol dimethylether, 0.5 m1. of an ethyl acetate solution containing 109.5 g. of hydrogen chloride per 1000 ml. and 0.33 g. (0.011 mol.) of paraformaldehyde is heated to -90 C. and maintained at that temperature for one hour. The resulting mixture is cooled to room temperatur and concentrated to one-third of its volume under reduced pressure, diluted with water, then allowed to crystallize. The product is filtered off and recrystallized from water, to yield the desired 6-chloro-7-sulfamyl-3,4-dihydro-ZH-[1,2,4]-benzothia-diazine-l,l-dioxide, M.P. 266268 C.; yield 1.4 g.

By replacing paraformaldehyde by 0.84 g. of 1,1-dimethoxymethane and proceeding as above, the same compound is obtained.

Following are working examples, illustrative of, but in no way intended to limit the present invention. Unless otherwise indicated, all parts, wherever given in the specification, are parts by weight. All sieve sizes are US. Standard sieve sizes.

Example 1 10,000 tablets Material and formula: (grams) 6 chloro 3,4 dihydro 7 sulfamyl 2H- 1,2,4 benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 150.00 Reserpine 1.00 Lactose USP 1191.50 Acacia 75.00 Talc USP 75.00 Magnesium stearate USP 7.50

50% 3A alcohol, q.s.

Procedure for preparation.Triturate the reserpine with grams of lactose and force through a No. 50 screen. Incorporate the remainder of the lactose, the acacia and the hydrochlorothiazide. Granulate with sufiicient 50% 3A alcohol. Pass the moist mass through a No. 10 screen and dry wit-h circulating air at F. until moisture content is 3 percent. Break the granules on a No. 16 screen and mix with the talc and magnesium stearate. Compress into tablets weighing mg., using inch punches and dies.

3 Example 2 10,000 tablets Material and formula: (grams) 6 chloro-3,4-dihydro-7-sulfarnyl-2H-l,2,4- benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 250.00 Reserpine 2.50 Lactose USP 1165.40 Corn starch (anhydrous basis) 67.10 Stearic acid powder USP 15.00

Purified water, q.s.

Procedure for preparation-Triturate the reserpine with 100 grams of lactose. Pass the mixture through a No. 50 screen and combine with the hydrochlorotliiazide, 38.5 grams of dry corn starch and the remainder of the lactose. Mix thoroughly. Suspend 28.6 grams of dry corn starch in 35 ml. of purified water and add 140 ml. boiling purified water to form a paste. Granulate the mixed powders with this paste, using additional water if necessary. Pass the wet mass through a No. 8 screen and dry at 100 F. with circulating air. Break the granules on a No. 14 screen and mix with the stcaric acid powder. Compress into tablets weighing 150 mg, using inch punches and dies.

Example 3 10,000 tablets Material and formula: (grams) 6 chloro-3,4-dihydro-7-sulfamyl-2H-1,2,4-

benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 250.00 Reserpine triturate 20.60 Lactose spray dried 1123.00 Corn starch (anhydrous basis) 67.10 Silicon dioxide (Cab-O-Sil) 30.00 Magnesium stearate USP 9.00 D & C Brown No. 1 0.30 Purified water, q.s.

50% 3A anhydrous alcohol, q.s.

Procedure for preparation.--Mix together the reserpine triturate 5%, the hydrochlorothiazide, silicon dioxide, magnesium stearate and 38.5 grams of dried corn starch. Dissolve the color in 35 ml. of purified water and suspend 28.6 mg. of dried corn starch in this solution. Make a paste by adding 140 ml. of purified water. Granulate the mixed powders with this paste, using sufficient 50% 3A alcohol to complete the granulation. Pass the moist mass through a No. screen and dry with circulating air at 100 F. until moisture is 2 percent. Break the granules on a N0. 14 screen and compress into tablets weighing 150 mg, using inch punches and dies.

Example 4 10,000 tablets Material and formula: grams) 6 chlor0-3,4-dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 250.00 Rescinnamine 5.00 Mannitol 667.50 Gelatin 20.00 Talc USP 50.00 Magnesium stearate USP 7.50

Purified water, q.s.

Procedure for preparation-Mix the resinnamine with 50 grams of mannitol and force the mixture through a No. 50 screen. Mix the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in 130 ml. purified water, using heat. Granulate the hydrochlorothiazide-mannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 110 F. until moisture content is less than 0.5%. Break the granules on a No. 16 screen and mix them with the talc, magnesium stearate and the rescinnamine-mannitol mixture. Compress into tablets weighing mg, using A inch punches and dies.

Example 5 10,000 tablets Material and formula: (grams) 6 chloro-3,4-dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 250.00 Rescinnamine 10.00 Mannitol 1120.00 Gelatin 30.00 Talc USP 5.00 Magnesium stearate USP 15.00

Purified water, q.s.

Procedure for preparation-Mix the resciimamine with 75 grams of mannitol and force through a No. 50 screen. Combine the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in 180 ml. purified water, using heat. Granulate the hydrochlorothiazidemannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at F. with circulating air until moisture content is less than 0.5 percent. Break the granules on a No. 14 screen and mix with the talc, magnesium stearate and the rescinnaminemannitol mixture. Compress into tablets weighing 150 mg, using inch punches and dies.

Example 6 10,000 tablets Material and formula: grams) 6 chloro-3,4-dihydro-7-sulfamyl-2H-l,2,4- benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 125.00 Rescinnamine 5.00 Mannitol 790.00 Gelatin 20.00 Talc USP 50.00 Magnesium stearate 10.00

purified water, q.s.

Procedure for Preparation-Mix the rescinnamine with 50 grams of mannitol and force the mixture through a N0. 50 screen. Mix the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in ml. purified water, using heat. Granulate the hydrochlorothiazide-mannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 110 F. until moisture content is less than 0.5 percent. Break the granules on a No. 16 screen and mix them with the talc, magnesium stearate and the rescinnamine-mannitol mixture. Compress into tablets weighing 100 mg, using inch punches and dies.

Example 7 10,000 tablets 50% 3A alcohol, q.s.

Procedure for preparation.Triturate the deserpidine with 100 grams of lactose and force through a No. 50 screen. Combine with the hydrochlorothiazide, tragacanth and the remainder of the lactose in a suitable mixer and mix for 30 minutes. Granulate the mixed powders with sufiicient 50% 3A alcohol. Pass the moist mass through a No. screen and dry at 100 F. with circulating air until moisture content is 3 percent. Break the granules on a No. 14 screen and mix with the corn starch, talc, and magnesium stearate. Compress into tablets weighing 150 mg., using inch punches and dies.

Example 8 10,000 tablets Material and formula: (grams) 6 chloro-3,4-dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 250.00 Deserpidine 2.50 Lactose spray dried 1232.50 Magnesium stearate USP 15.00

Procedure for preparation.Triturate the deserpidine with 100 grams of lactose and pass the mixture through a No. 50 screen. Combine with the hydrochlorothiazide, magnesium stearate and the remainder of the lactose in a suitable mixer and mix for 30 minutes. Compress into tablets weighing 150 mg, using W inch punches and dies.

Example 9 10,000 tablets Material and formula: (grams) 6-chloro-3,4-dihydro 7 sulfamyl-2H-1,2,

4-benzothiadiazine 1,1 dioxide (hydro- Purified water, q.s.

Procedure for preparation.-Triturate the deserpidine with 300 grams of lactose and force through a No. 50 screen. Combine this material with the hydrochloro-thiazide and the remainder of the lactose. Dissolve the sucrose in 125 ml. of purified water, using heat. Granulate the mixed powders with the resultant syrup, using additional water if necessary. Pass the moist mass through a No. 8 screen and dry at 100 F. until moisture content is about 2 percent. Break the granules on a No. 12 screen and mix with the corn starch, talc :and magnesium stearate. Compress into tablets weighing 250 mg., using %,2111611 punches and dies.

Example 10 10,000 tablets Material and formula: (grams) 6-chloro-3,4-dihydro-7-sulfamyl 2H 1,2,4- benzothiadiazine-l,l-dioxide (hydrochlorothiazide) 500.00 Reserpine 0.50 Lactose USP 842.00 Acacia 75.00 Talc USP 75.00

Magnesium stearate USP 7.50

50% 3A alcohol, q.s.

6 Example 11 10,000 tablets Material and formula: (grams) 6-chloro 3,4 dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine-l,l-dioxide (hydrochlorothiazide) 500.00 Reserpine 10.00 Lactose USP 907.90 Corn starch (anhydrous basis) 67.10 Stearic acid powder USP 15.00

Purified water, q.s.

Procedure for preparation.-Triturate the reserpine with grams of lactose. Pass the mixture through a No. 50 screen and combine with the hydrochlorothiazide, 38.5 grams of dry corn starch and the remainder of the lactose. Mix thoroughly. Suspend 28.6 grams of dry corn starch in 35 ml. of purified water and add ml. boiling purified water to form a paste. Granulate the mixed powders with this paste, using additional water if necessary. Pass the Wet mass through a No. 8 screen and dry at 100 F. with circulating air. Break the granules on a No. 14 screen and mix with the stearic acid powder. Compress into tablets weighing mg, using 03 inch punches and dies.

Example 12 10,000 tablets Material and formula: (grams) 6-chloro-3,4-dihydro 7 sulfamyl-2H-1,2,

4-benzothiadiazine-1,l dioxide (hydrochlorothiazide) 1000.00

Reserpine triturate 5% 20.60 Lactose spray dried 373.00 Corn starch (anhydrous basis) 67.10 Silicon dioxide (Cab-O-Sil) 30.00 Magnesium stearate USP 9.00 D & C Brown No. 1 0.30

Purified water, q.s. 50% 3A anhydrous alcohol, q.s.

Procedure for preparation.Mix together the reserpine triturate 5%, the hydrochlorothiazide, silicon dioxide, magnesium stearate and 38.5 grams of dried corn starch. Dissolve the color in 35 ml. of purified Water and suspend 28.6 mg. of dried corn starch in this solution. Make a paste by adding 140 ml. of pun'fied Water. Granulate the mixed powders with this paste, using suflicient 50% 3A alcohol to complete the granulation. Pass the moist mass through a No. 10 screen and dry with circulating air at 100 F. until moisture is 2 percent. Break the granules on a No. 14- screen and compress into tablets weighing 150 mg, using W inch punches and dies.

Example 13 10,000 tablets Material and formula: (grams) 6-chloro-3,4-dihydro-7-sulfamyl 2H 1,2,4- benzothiadiazine-1,1-dioxide (hydrochlorothiazide) 500.00 Rescinnarnine 50.00 Mannitol 372.50 Gelatin 20.00 Talc USP 50.00

Magnesium stearate USP 7.50

Purified water, q.s.

ture. Compress into tablets weighing 100 mg, using inch punches and dies.

Example 14 10,000 tablets Material and formula: (grams) 6-chloro-3,4dihydro 7 sulfamyl-ZH-LZ,

4-benzothiau inc-1,1 dioxide (hydro- Purified Water, q.s.

Procedure for prcparation.Mix the rescinuamine with 75 grams of mannitol force through a No. 50 screen. Combine the remainder of the mannitol with the hydrochlorothiazide. Bissolve the gelatin in 180 ml. purified water, using h-za Granulute the hydrochlorothiaziclemar itol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 110 F. with circulating air until moisture content is less than 0.5 percent. the granules on a No. 14 screen and mix with the tale, magnesium stearate and the rescinnamine-mannitol mixture. Compres into tablets weighing 150 mg, using 9 inc punches and dies.

Example 15 10,000 tablets Material and formula: grams) 6-chloro-3,4-dihydro-7-sulfamyl 2H 1,2,4- benzothiadiazine-l,l-dioxide (hydrochloro- Purified water, q.s.

Procedure for preparation-Mix the rescinnamine with 50 grams of mannitol and force the mixture through a No. 50 screen. Mix the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in 130 ml. purified water, using heat. Granular-e the hydrochlorothiazide-mannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 100 F. until moisture content is less than 0.5 percent. Break the granules on a No. 16 screen and mix them with the talc, magnesium stearate and the resciunamine-mannitol mixture. Compress into tablets weighing 100 mg, using f g inch punches and dies.

Example 16 10,000 tablets Material and formula: grams) o-chloro-3,4-dihydro-7-sulfamyl 2H 1,2,4- benzothiadiazine-1,1-dioxide (hydrochlorothiazide) 500.00 Deserpidine 0.50 Lactose spray dried 842.00 Tragacanth USP 30.00 Corn starch 75.00 Talc USP 45.00 Magnesium stearate USP 7.50

50% 3A alcohol, q.s.

and magnesium stearate. Compress into tablets weighing 150 mg, using inch punches and dies.

Example 17- ;10,000 tablets Material and formula: (grams) 6-chloro-3,4-dihydro-7-sulfamyl 2H-l,2,4- benzothiadia'zine 1,1 dioxide (hydrochlorothiazide) 500.00 Deserpidine 10.00 Lactose USP 1580.00 Sucrose USP 125.00 Corn starch 125.00 Talc USP 125.00 Magnesium stearate USP 25.00

Purified water, q.s.

Procedure for prep-aration.--Triturate the deserpidine with 300 grams of lactose and force through a No. 50 screen. Combine this material with the hydrochlorothiazide and the remainder of the lactose. Dissolve the sucrose in 1215 ml. of purified water, using heat. Granulate the mixed powders with the resultant syrup, using additional water if necessary. Pass the moist mass through a No. 8 screen and dry at F. until moisture content is about 2 percent. Break the granules on a No. 12 screen and mix with the corn starch, talc and magnesium stearate. Compress into tablets weighing 250 mg, using inch punches and dies.

chloro-thiazide) 1000.00 Deserpidine 2.50 Lactose spray dried 482.50 Magnesium stearate USP 15.00

Procedure for preparation.-Triturate the deserpidine with 100 grams of lactose and pass the mixture through a No. 50 screen. Combine with the hydrochlorothiazide, magnesium stearate and the remainder of the lactose in a suitable mixer and mix for 30 minutes. Compress into tablets weighing mg, using inch punches and dies.

This invention may be variously otherwise embodied within the scope or" the appended claims.

What is claimed is:

1. A pharmaceutical composition, in oral dosage unit form, comprising about 1 to about 20 ercent of 6-chloro- 7-sulfamyl-3,4-dihydro-2 H [1,2,4] benzothiadiazine- 1,1-dioxide, and about 0.005 to about 0.5 percent indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

2. A pharmaceutical composition of claim 1 in oral dosage unit form comprising about 2.5 to about 10 percent of 6-chloro-7-sulfamy1-3,4-dihydro 2 H [1,2,4]- -benzothiadiazine-1,l-dioxide, and about 0.01 to about 0.4 percent alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

3. A pharmaceutical composition of claim 2, in oral dosage unit form, comprising about 2.5 percent of 6-halo- 7-sulfamyl-3,4-dil1ydro-2 H [1,2,4] benzothiadiazine- 1,1-dioxide and about 0.01 percent indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

4. A pharmaceutical composition, in oral dosage unit form, comprising about 10 to about 200 milligrams of 6- chloro-7-sulfamyl-3,4-dihydro 2 H [1,2,4] benzothiadiazine-Ld-dioxide, and about 0.05 to about 5.0 milligrams indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

5. A pharmaceutical composition of claim 4, in oral dosage unit form, comprising about 10 to about 2 00 milligrams of 16-chloro-7-sulfamyl-'3,4dihydro 2-H [1,2,4]- benzot-hiadiazine-1,1dioxide and about 0.05 to about 5.0 milligrams ind-ole alkaloid of the Apocynaceae family selected 'from the group consisting of reserpine, deserpidine and rescinnamine.

6. A pharmaceutical composition of claim 4, in oral dosage unit form, comprising about 25 to about 100 milligrams of 6-chloro-7-sulfamyl-3,4-dihydro 2 H-[ 1,2,4]- lbenzothiadiazine-l,l-dioxide and about 0.1 to about 0.4 milligram indole alkaloid of vthe Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnam-ine.

7. A pharmaceutical composition of claim 4, in oral dosage unit form, comprising about 25 milligrams of 6 chloro-7-1su'l-famyk3,-4-dihydro-2 H [1,2,4] benzothiadiazine-1,l-di-oxide and about 0.1 to about 0.5 milligram indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

References Cited UNITED STATES PATENTS 3,288,678 1'1/!l'966 De Stevens.

ALBERT T. MEYERS, Primary Examiner.

S. J. FRIEDMAN, Assistant Examiner.

Disclaimer 3,379,612.Ge0rge De Stevens, and Lincoln Harvey Werner, Summit NJ. PHAR- MACEUIICAL COMPOSITIONS OF G-CHLORO-I-SULFAMYL -3, 4-DIHYDRO-2H-[l,2,4]BENZOTHIADIAZINE 1,1-DIOXID assignee, Ciba-Geigv Corp.

The term of this patent subsequent to Mar. 31, 1981, has been disclaimed.

[0 9mm Gazette May 19, 1981.] 

